System And Method Of Administering A Pharmaceutical Gas To A Patient

ABSTRACT

Methods and systems for delivering a pharmaceutical gas to a patient. The methods and systems provide a known desired quantity of the pharmaceutical gas to the patient independent of the respiratory pattern of the patient over a plurality of breaths every nth breath, where n is greater than or equal to 1. The pharmaceutical gases include CO and NO, both of which are provided as a concentration in a carrier gas. The gas control system determines the delivery of the pharmaceutical gas to the patient to result in the known desired quantity (e.g. in molecules, milligrams or other quantified units) of the pharmaceutical gas being delivered. Upon completion of that known desired quantity of pharmaceutical gas over a plurality of breaths, the system can either terminate, continue, activate and alarm, etc.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. § 120 of U.S. patentapplication Ser. No. 14/551,186, filed Nov. 24, 2014, which is acontinuation under 35 U.S.C. § 120 of U.S. patent application Ser. No.13/331,807, filed Dec. 20, 2011, now U.S. Pat. No. 8,893,717, issuedNov. 25, 2014, which is a continuation-in-part under 35 U.S.C. § 120 ofU.S. patent application Ser. No. 12/430,220, filed Apr. 27, 2009, nowU.S. Pat. No. 8,091,549, issued Jan. 10, 2012, and U.S. patentapplication Ser. No. 13/287,663, filed Nov. 2, 2011, now U.S. Pat. No.8,517,015, issued Aug. 27, 2013, and U.S. patent application Ser. No.13/284,433, filed Oct. 28, 2011, now U.S. Pat. No. 8,397,721, issuedMar. 19, 2013, which are continuations of U.S. patent application Ser.No. 11/231,554, filed Sep. 21, 2005, now U.S. Pat. No. 7,523,752, issuedApr. 28, 2009, the entire disclosures of which are hereby incorporatedby reference herein.

BACKGROUND

The present invention relates to methods and systems for administering apharmaceutical gas to a patient and, more particularly, to methods andsystems for introducing carbon monoxide CO or nitric oxide NO to apatient in a predetermined quantity.

The normal or conventional way of giving a pharmaceutical drug to apatient is to prescribe the dose based on the quantity of drug (usuallyin weight) per unit weight of the patient (e.g. mg/Kg) with the dosebeing specified to be delivered over a period of time or being repeatedat specified intervals of time. This allows the user to control thequantity of drug and ensures the quantity of drug being delivered is inproportion to the patient's size. This is to reduce the patient topatient variability in response to the drug due to the size of thepatient i.e. a 7 Kg baby will not get the same quantity of drug as a 80Kg adult.

In recent times there have been a number of gases which have been shownto have pharmaceutical action in humans and animals. Examples includeNitric Oxide (NO) Zapol et al U.S. Pat. No. 5,485,827 and more recentlyCarbon Monoxide (CO) Otterbein et al (U.S. Published Patent ApplicationNo. 2003/0219496). In the Otterbein patent application, CO is describedas having a pharmacological action in a number of medical conditionsincluding ileus and vascular disease.

In these cases, the carbon monoxide gas needs to be delivered to thepatients' alveoli where it can move across the alveolar membrane andinto the blood stream where its action can take effect. The currentdosing used in these cases is for the patient to breath at a specifiedconcentration of CO in ppm for a specified period of time. Accuratedosing of CO for these treatments is important as CO reacts with thehemoglobin in the blood to form carboxyhemoglobin which means thehemoglobin is no longer able to carry oxygen to the tissues of the body.If too much CO is given, the patient may exhibit the toxic effects of COfor which it is usually known.

There is a tight window for CO delivery between the therapeutic leveland the level that causes carboxyhemoglobin above safe levels. Up untilnow CO has been delivered as a constant concentration in the gasbreathed by the patient/animal for a specified period of time. Forexample in reference 3 of the Otterbein publication, (Example 2 pg 13)the therapeutic dose delivered to mice for the treatment of ileus was250 ppm of CO for 1 hour.

However, this method of dosing CO can be associated with largevariability in the actual dose being delivered to the animal/humansalveoli. This variability is because the quantity of CO being deliveredto the animal/patient is dependent on a number of variables including,but not limited to, the patients tidal volume, respiratory rate,diffusion rate across the alveolar and ventilation/perfusion (V/Q)matching.

The amount of CO delivered into a patient's alveoli can be determined bythe ideal gas law as shown in the following equation:

N=PV/(R _(u) T)   (1)

Where: N is the number of moles of the gas (mole) P is the absolutepressure of the gas (joule/m³) V is the volume of the particular gas(m³), R_(u) is the universal gas constant, 8.315 joule/mole-K and T isthe absolute temperature (K).

If we assume atmospheric pressure (101,315 joule/m³) and 20° C. (293 K)as the temperature and we express the volume in mL (10⁻⁶ m³), thenequation (1) reduces to:

N=4.16×10⁻⁵ V (moles)   (2)

Equation (2) can be used to calculate the number of moles of gasdelivered to a patient's alveolar volume over a period of time whengiven a specified concentration by using the following equation:

N _(CO) =RR·t·C _(CO)·10⁻⁶·4.16×10⁻⁵ V _(a)   (3)

Where; C_(CO) is the concentration of CO (ppm), V_(a) is the alveolarvolume (mL), RR is the respiratory rate (BPM) and t is the time inminutes.

For example, if the CO dose for ileus in humans was 250 ppm of CO forone hour (60 minutes), the alveolar volume is 300 mL and the patientsrespiratory rate is 12 breaths per minute (bpm) then the amount of COgas in moles delivered to the patients alveoli over that period wouldbe:

N _(CO)=12—60·250·10⁻⁶·4.16×10⁻⁵·300=2.25×10⁻³ moles

This can be converted into the mass of drug delivered (M_(CO)) using thegram molecular weight of CO which is 28 as shown in the followingequation:

M _(CO) =N _(CO)·28=63×10⁻³ g=63 mg   (4)

However, although this works for a given set of assumptions, aspontaneous patient's respiratory rate can vary widely from perhaps 8 to20 breaths per minute depending on circumstances and the patient'salveolar volume per breath can also vary significantly from say 200 to400 mL depending on the metabolic need. These variables can have adramatic effect on the amount of gaseous drug being delivered to thepatient over the same period of time. For instance, if the patientsrespiratory rate was 8 bpm and the alveolar volume was 200 mL, the COdose delivered to the patients alveoli would have been 27.8 (mg).Likewise if the patients respiratory rate was 20 bpm and the alveolarvolume was 400 mL, then the dose delivered to the patients alveoli wouldhave been 139.2 (mg) thus representing a five-fold difference in theamount of drug being delivered.

This means, in the example of CO, the quantity of gaseous drug a patientgets as measured in grams could vary substantially depending on thepatient's ventilation pattern. For a dose based on constantconcentration and time, the effect of these variables could mean that anindividual patient could get significantly higher or lower doses of COin grams and this could result in either high unsafe levels ofcarboxyhemoglobin or doses too low to be effective. Although not all thegaseous drug delivered to the alveoli will be taken up by the body'sbloodstream (due to variables such as cardiac output and the diffusioncoefficient of the gas) controlling the amount delivered to the alveolitakes away a major source of variability.

In addition, there is a need to administer NO to a patient in apredetermined quantity as described in “Cell-free hemoglobin limitsnitric oxide bioavailabllity in sickle-cell disease”, Nature Medicine,Volume 8, Number 12, December 2002, pages 1383 et seq. This paperdescribes the use of inhaled NO to react with cell free hemoglobin toform plasma methemoglobin and so reduce the ability of the cell freehemoglobin in the plasma to consume endogenously produced NO (FIG. 5,page 1386). The quantity of NO delivered to the patient blood needs tobe equivalent to the amount of cell free hemoglobin that is in thepatients plasma. The amount of NO delivered to a sample of sickle cellpatients was 80 ppm of NO for 1.5 hours. However, there was variabilityin the amount of methemoglobin produced in individual patients as shownby the error bars on FIG. 4b. So, in a similar way to the CO example, aknown quantity of NO needs to be delivered to a patient to provide thedesired therapeutic effect and again it is important to remove anyvariability of delivery because of differences in the individualpatient's respiratory pattern.

Accordingly, it would be advantageous to have a system and method ofintroducing pharmaceutical gases (such as carbon monoxide and nitricoxide) that allows for the precise control of a known quantity of thepharmaceutical gas to be delivered to the patients alveoli and which isnot subject to change based on the patients respiratory patterns.

SUMMARY

Accordingly, the present invention relates to systems and methods foradministering a pharmaceutical gas, such as carbon monoxide and nitricoxide, that allows a clinician to determine and control the desiredquantity of the gas to be delivered to the patient. The methodsdetermine the desired quantity of the pharmaceutical gas to beadministered to the patient and then administers the desired quantity ofthe pharmaceutical gas irrespective of the patients respiratorypatterns. If the prescription is specified as a total quantity of drug,then the method terminates the administration of the pharmaceutical gaswhen the desired total quantity has been administered to the patient.

Thus, by the methods of various embodiments of the present invention,the amount of the pharmaceutical gas is delivered to the patient as aknown desired quantity and that known desired quantity can be expressedin various units of measurement, such as, but not limited to, the weightof drug in micrograms (μg), milligrams (mg), grams (g) etc., the molesof drug in nanomoles (nM), micromoles (μM), millimoles (mM) moles (M)etc, or the volume of drug, at a known concentration or partialpressure, in microliters (μL), milliliters (mL), liters (L) etc. Thedesired quantity of the pharmaceutical gas can also be expressed as anamount per unit of time for a period of time such as mg/hour for 2hours.

One or more embodiments of the invention also include systems foradministering a pharmaceutical gas, such as carbon monoxide or nitricoxide, and the system includes an inlet means that can be connected tothe source of the pharmaceutical gas and deliver the gas to a patient bymeans of a patient device. That patient device can be any device thatactually introduces the pharmaceutical gas into the patient such as anasal cannula, endotracheal tube, face mask or the like. There is also agas control system that controls the introduction of the quantity of apharmaceutical gas from the gas source through the patient device.Again, therefore, the system provides a known quantity of gas to thepatient.

As such, embodiments of the present invention allows a user to set adesired quantity of gaseous drug to be delivered to a patient's alveoliand for the system to then deliver that gaseous drug over multiplebreaths until the prescribed amount has been delivered.

As a further embodiment, the system and method may simply provide analarm, visual and/or audible, to alert the user when the predeterminedtotal quantity of the pharmaceutical gas has been administered to thepatient and not actually terminate that administration. As such, theuser is warned that the total predetermined desired quantityadministered over the plurality of breaths has now been delivered to thepatient so that the user can take the appropriate action, including acloser monitoring of the patient.

These and other features and advantages of the present invention willbecome more readily apparent during the following detailed descriptiontaken in conjunction with the drawings herein.

One or more embodiments of the invention are directed to methods ofadministering a therapy gas to a patient, the therapy gas being at leastone gas selected from CO and NO. The methods comprise determining adesired total quantity of therapy gas to be administered to the patientover a period of time over a plurality of breaths. A quantity of thetherapy gas is administered to the patient during inspiration everyn^(th) breath of the plurality of breaths, wherein n is 1 or greater.The quantity of the therapy gas varied per n^(th) breath to ensure thatthe desired total quantity over the period of time is administeredindependent of the respiratory pattern of the patient.

In some embodiments, the quantity of therapy gas per n^(th) breath is inthe range of a minimum quantity of therapy gas per breath and a maximumquantity of therapy gas per breath. In detailed embodiments, thequantity of therapy gas per nth breath is a function of one or more of afirst respiratory rate, a first tidal volume of the patient and thepatient's ideal body weight. In specific embodiments, the quantity oftherapy gas per n^(th) breath to be delivered is greater than theminimum quantity of therapy gas per breath and less than the maximumquantity of therapy gas per breath, the quantity of therapy gas perbreath is administered on the n^(th) breath, or when the quantity oftherapy gas per nth breath is less than the minimum quantity of therapygas per breath, administration of the quantity of therapy gas per nthbreath is skipped for that n^(th) breath, or when the quantity oftherapy gas per n^(th) breath is greater than the maximum quantity oftherapy gas per breath, one or more of an alarm is triggered or themaximum quantity is delivered on the nth breath and a difference betweenthe quantity of therapy gas per n^(th) breath to be delivered and themaximum quantity of therapy gas per breath is carried to one or moresubsequent breaths. In certain embodiments, when the quantity of therapygas per n^(th) breath is skipped, a new quantity of therapy gas pern^(th) breath is calculated. In detailed embodiments, when the quantityof therapy gas per n^(th) breath is greater than the maximum quantity oftherapy gas per breath, the maximum quantity of therapy gas per breathis administered on the n^(th) breath and the difference between thequantity of therapy gas per n^(th) breath and the maximum quantity oftherapy gas per breath is added to one or more subsequent breaths.

In one or more embodiments, n is 2 or greater and the therapy gas isdelivered during the n^(th) breath. In some embodiments, no therapy gasis administered during the breaths that are not n^(th) breaths. Indetailed embodiments, the quantity of therapy gas per n^(th) breath isin the range of a minimum quantity of therapy gas per breath and amaximum quantity of therapy gas per breath. In specific embodiments, thequantity of therapy gas per n^(th) breath is a function of one or moreof a first respiratory rate, a first tidal volume of the patient and thepatient's ideal body weight.

In some embodiments, when the quantity of therapy gas per n^(th) breathto be delivered is greater than the minimum quantity of therapy gas perbreath and less than the maximum quantity of therapy gas per breath, thequantity of therapy gas per n^(th) breath is administered on the n^(th)breath, or when the quantity of therapy gas per n^(th) breath is lessthan the minimum quantity of therapy gas per breath, administration ofthe quantity of therapy gas per n^(th) breath is skipped for that n^(th)breath, or when the quantity of therapy gas per n^(th) breath is greaterthan the maximum quantity of therapy gas per breath, one or more of analarm is triggered or the maximum quantity is delivered on the n^(th)breath and a difference between the quantity of therapy gas per n^(th)breath to be delivered and the maximum quantity of therapy gas perbreath is carried to one or more subsequent breaths. In one or moreembodiments, when the quantity of therapy gas per n^(th) breath isskipped, a new quantity of therapy gas per n^(th) breath is calculated.Detailed embodiments further comprise repeating the administration ofthe therapy gas on one or more subsequent breaths. In specificembodiments, when the quantity of therapy gas per n^(th) breath isgreater than the maximum quantity of therapy gas per breath, the maximumquantity of therapy gas per breath is administered on the n^(th) breathand the difference between the quantity of therapy gas per nth breathand the maximum quantity of therapy gas per breath is added to one ormore subsequent breaths. Certain embodiments further comprise repeatingthe administration of the therapy gas on one or more subsequent breaths.

In some embodiments, when the quantity of therapy gas per nth breath isgreater than the maximum quantity of therapy gas per breath, the maximumquantity of therapy gas per breath is administered on the n^(th) breathand the difference between the quantity of therapy gas per n^(th) breathand the maximum quantity of therapy gas per breath is administered overone or more subsequent breaths that are not an n^(th) breath. Inspecific embodiments, the therapy gas is delivered to the patient'salveoli. In certain embodiments, the therapy gas is delivered to thepatient during the first half of the inspiratory cycle.

Additional embodiments are directed to methods of administering atherapy gas to a patient, the therapy gas being at least one of CO andNO. A desired total quantity of therapy gas to be administered to thepatient over a period of time over a plurality of breaths is determined.A quantity of therapy gas to be delivered to the patient per n^(th)breath is calculated, where calculating the quantity based on one ormore of respiratory rate and quantity already given to the patient. Thequantity of the therapy gas administered to the patient's alveoli duringthe first half of the inspiratory cycle for every n^(th) breath of theplurality of breaths, n being greater than 1 averaged over the period oftime. Steps b) and c) are repeated varying the quantity of the therapygas per n^(th) breath to ensure that the desired total quantity over theperiod of time is maintained independent of the respiratory pattern ofthe patient.

Some embodiments further comprise comparing the quantity of therapy gasto be delivered to determine if the quantity is in the range of aminimum quantity and a maximum quantity. In detailed embodiments, if thequantity of therapy gas to be delivered is lower than the minimumquantity, then the quantity of therapy gas delivered during the breathis zero and the quantity of therapy gas to be delivered is added to oneor more subsequent breaths. In specific embodiments, wherein if thequantity of therapy gas to be delivered is greater than the maximumquantity, then performing one or more of activating an alarm,determining the difference between the quantity of therapy gas to bedelivered and the maximum quantity, administering the maximum quantityor adding the difference between the quantity of therapy gas to bedelivered and the maximum quantity to one or more subsequent breaths.

Further embodiments of the invention are directed to systems foradministering a therapy gas to a patient having a respiratory pattern,the therapy gas being at least one gas selected from CO and NO. Thesystem comprises an inlet to connect to a source of therapy gas, anoutlet to connect to a device that introduces the therapy gas to thepatient, a setting control to determine the desired quantity of therapygas to be delivered to the patient over a plurality of breaths, and agas control system to deliver the desired quantity of the therapy gas tothe patient during inspiration by the patient over the plurality ofbreaths independent of the patient's respiratory pattern. The gascontrol system is configured to calculate a quantity of therapy gas tobe delivered to the patient per n^(th) breath, calculating the quantitybased on one or more of respiratory rate and quantity already given tothe patient, administer the quantity of the therapy gas to the patient'salveoli during the first half of the inspiratory cycle for every n^(th)breath of the plurality of breaths, n being greater than 1 averaged overthe period of time, and repeat steps a) and b) varying the quantity ofthe therapy gas per breath to ensure that the desired total quantityover the period of time is maintained independent of the respiratorypattern of the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are views of a front panel of an apparatus for carryingout the present invention showing different user options;

FIG. 3 is a schematic view of the present invention used with aspontaneously breathing patient;

FIG. 4 is a schematic view of the present invention used with a patientbeing breathed by means of a ventilator; and

FIG. 5 shows a flowchart of an exemplary method of administering atherapy gas to a patient according to one or more embodiments of theinvention.

DETAILED DESCRIPTION

In the following detailed description, CO is used as the pharmaceuticalgas but the description can also be valid for NO. Referring now to FIG.1, there is shown a front view of an apparatus that can be used incarrying out the present invention. As can be seen, there is a frontpanel 10 that can be a part of the apparatus and on that panel there areinput setting knobs and displays which allow the user to set and monitorthe amount of CO that is to be delivered to the patient.

The means for determining the desired quantity of CO to be delivered isby means of an input setting knob 12 with the set amount being shown onthe setting display 8. The units shown in FIG. 1 are in milligrams perkilogram that is, the units are measured in a dosage per kilogram of thepatient's ideal body weight. Along with that input, there is a furtherinput 14 whereby the user can enter the patient's ideal body weight inkilograms with the amount also displayed on the setting display 8. Withthose inputs, the user can set the quantity of the pharmaceutical gas tobe administered to the patient in proportion to the size of the patientand which reduces the patient to patient variability in response to thepharmaceutical gas due to the size of the patient, i.e. a 7 kilogrambaby will not be administered the same quantity of the pharmaceuticalgas as a 80 kilogram adult.

The front panel 10 also has a monitor display 6 which can display totaldose of CO (mg) to be delivered (shown at 16) as calculated formultiplying the dosage/kg by the patients ideal body weight in kg.

Once the desired quantity of gaseous drug has been set on the device thesystem then determines the amount of pharmaceutical gas that is to bedelivered in each breath and the amount of time and/or the number ofbreaths that it will take to deliver the total desired quantity of drug.The monitor display 6 can also display a running total of the delivereddose of CO (mg) (shown at 17) as it is delivered to the patient so theuser can monitor the progress of the treatment. This can be updated eachbreath as more pharmaceutical gas is delivered.

As stated, the units illustrated in FIG. 1 are in metric units, however,it can be seen that other units of mass and volume could be used incarrying out the present invention i.e. ounces and cubic inches andother designs of a front panel can be used as will later be understood.

Referring to FIG. 2, there is shown a similar front panel 10 for theapparatus as shown in FIG. 1 but illustrating a different user settingoption. The desired quantity of CO to be delivered to the patient isprescribed as a rate of delivery by means of input setting knob 13 andis in units of mg/hr of CO to be delivered. In this option, the devicealso allows the time duration (in hours) of treatment to be set by ameans of an input setting knob 15. If required, the input setting byinput setting knob 15 could be set to continuous where the dose per hourwould run continuously until the user changed the setting. With theseinput settings, the apparatus can calculate and display the desiredquantity of the pharmaceutical gas to be administered to the patient.

Also, as in FIG. 1, the front panel 10 also has a monitor display 6which can display total dose of CO (mg) to be delivered (shown at 16) ascalculated by multiplying the dosage/hr by the total time duration(hr.). Once the desired quantity of pharmaceutical gas has been set onthe device, the system then determines the amount of pharmaceutical gasto be delivered in each breath and the amount of time and/or the numberof breaths that it will take to deliver the total desired quantity ofdrug. As before, the monitor display 6 can display a running total ofthe delivered dose of CO (mg) (shown at 17) as it is delivered to thepatient so the user can monitor the progress of the treatment. This canbe updated each breath as more pharmaceutical gas is delivered.

As can be appreciated, FIGS. 1 and 2 illustrate two of the many optionsfor setting the desired quantity and duration of pharmaceutical gastherapy. These options are not meant to be exhaustive and there areother setting options described or that can be understood from thedetailed descriptions that follow.

Once the desired quantity of gaseous drug has been set on the device,the gas control system can then determine the amount of pharmaceuticalgas to be delivered in each breath and the amount of time and/or thenumber of breaths that it will take to deliver the desired quantity ofpharmaceutical gas.

There are a number of different approaches that the gas control systemcan use to determine the amount per breath and how long to deliver thatdose so the desired quantity of pharmaceutical gas is deliveredindependent of the respiratory pattern of the patient:

-   -   a) The user can set the quantity of pharmaceutical gas to be        delivered during each breath (M_(CO) breath) and the gas control        system calculates the number of breaths (n_(breaths)) which will        be required to deliver the total quantity of pharmaceutical gas        (M_(CO)) i.e.

n _(breaths) =M _(CO) /M _(CO breath)   (5)

Once the total number of breaths (n_(breaths)) required has beendetermined the value can be displayed on the front panel 12 by means ofdisplay 16 to inform the user of the number of breaths.

-   -   b) The user can set the number of breaths (n_(breaths)) that        will administer the total quantity of the pharmaceutical gas and        the system calculates the amount per breath (M_(CO breath)) to        be delivered.

M _(CO breath) =M _(CO) /n _(breaths) (mg)   (6)

Once the amount per breath (M_(CO breath)) to be delivered has beendetermined, the value can be displayed on the front panel 10 to informthe user of the amount.

-   -   (c) The user could set the time duration for which the treatment        is to be delivered over. The amount per breath would then be        determined by calculating the quantity per minute and then, by        monitoring the patients respiration rate in breaths per minute,        the amount of breath can be calculated. This calculation can be        repeated after every breath so any changes in the patients        respiratory rate does not affect the overall quantity of gaseous        drug being delivered.    -   d) If the desired quantity of pharmaceutical gas was entered as        a dose per Kg of the patient's ideal body weight (μg/kg) along        with the patient's ideal body weight (Kg) then the amount per        breath (M_(CO breath)) can be determined as a function of the        patient's ideal body weight (IBW), the set dose per kilogram        (M_(kg)) and the patient's monitored respiratory rate (RR) or        combinations thereof;

M_(CO) breath=f (IBW, M_(kg), RR) and the number of breaths can then becalculated as;

n _(breaths) =M _(CO) /M _(CO breath)   (7)

Once the amount per breath (M_(CO) breath) and the number of breaths(n_(breaths)) required to be delivered has been determined, the valuescan be displayed on the front panel 10 to inform the user of the amountsthe device has selected.

-   -   e) Instead of the ideal body weight (IBW) of the patient, the        height and sex of the patient could be entered (which is how IBW        is determined).    -   f) If the desired quantity of pharmaceutical gas per unit of        time is entered into the device, then the device can calculate        the quantity per breath to be delivered to the patient based on        the current monitored respiratory breath rate (as determined by        the breath trigger sensor). This quantity per breath can be        recalculated after every breath when new information on the        respiratory rate is available to ensure the quantity per unit of        time is maintained even if the patient respiratory breath        pattern changes over time.    -   g) There are also other ways of varying the quantity of        pharmaceutical gas delivered per breath to ensure the quantity        per unit of time is maintained even if the patients respiratory        rate changes. As used in this specification and the appended        claims, the term “varying the quantity” means that the        calculated quantity is a dynamic value capable of being        re-evaluated throughout administration of the therapy gas, not a        fixed value. It is possible that the amount of gas delivered for        each of the n^(th) breaths is the same, or the amount for nearly        every breath is the same. Varying the quantity does not mean        that the amount of therapy gas delivered on every n^(th) breath        is different from the previous or subsequent breaths, merely        that the value could be varied to compensate for changes in the        patient's breathing pattern. For example, varying the quantity        of therapy gas per breath may mean that the amount per breath is        cut in half when the respiratory rate of the patient doubles.

Another example is where the device has two different amounts ofdelivery per breath, a high amount and a low amount. The device chooseswhich one to use based on the calculated quantity per unit of time beingdelivered over the past number of breaths. If the amount per unit oftime is greater than required, it uses the low amount per breath untilthe situation corrects itself; likewise, if the quantity per unit oftime is running low, then the unit switches to the high amount perbreath.

The device can also have programmed limits which restrict the maximumand minimum values that can be selected for M_(CO) breath so that thesystem doesn't select inappropriately too high or too low values. Theselimits can be set to vary based on the patient's ideal body weight, orother indicator of the patient size such as the patient's height, or therespiratory rate of the patient.

The aforesaid information is sufficient for the system of the presentinvention to deliver the dose to the patient and to determine the amountper breath, time of administration or other parameter in order tocommence the administration of CO and to terminate that administrationwhen the user set quantity of the pharmaceutical gas has been deliveredto the patient.

Turning now to FIG. 3, there is shown a schematic of a system that canbe used to carry out the present invention when the patient is breathingspontaneously. As can be seen, there is a patient device 18 thatdelivers the dosage of the pharmaceutical gas from the gas deliverysystem 22 to the patient 41 via a gas conducting conduit 19. Asindicated, the patient device 18 can be any one of a variety of devicesthat actually directs the pharmaceutical gas into the patient and may bea nasal cannula, a mask, an endotracheal tube and the like.

With the FIG. 3 embodiment, there is a source of the pharmaceutical gasby means of a gas supply tank 20 containing the pharmaceutical gasgenerally in a carrier gas. When the pharmaceutical gas is carbonmonoxide, for example, the conventional, commercially available carriergas is air. The supply of carbon monoxide and air is provided inconcentrations of 3000 ppm however, concentrations within the range of1000 to 5000 ppm of CO in air are also possible alternatives. In thecase of NO as the pharmaceutical gas, the carrier gas is conventionallynitrogen and the typical available concentrations range from 100 ppm to1600 ppm.

Accordingly, from the supply tank 20, there is a tank pressure gauge 21and a regulator 23 to bring the tank pressure down to the workingpressure of the gas delivery system 22. The pharmaceutical gas entersthe gas delivery system 22 through an inlet 24 that can provide a readyconnection between that delivery system 22 and the supply tank 20 via aconduit. The gas delivery system 22 has a filter 25 to ensure nocontaminants can interfere with the safe operation of the system and apressure sensor 27 to detect if the supply pressure is adequate andthereafter includes a gas shut off valve 26 as a control of thepharmaceutical gas entering the delivery system 22 and to provide safetycontrol in the event the delivery system 22 is over delivering thepharmaceutical gas to the patient. In the event of such over delivery,the shut off valve 26 can be immediately closed and an alarm 42 soundedto alert the user that the gas delivery system has been disabled. Assuch, the shut off valve 26 can be a solenoid operated valve that isoperated from signals directed from a central processing unit includinga microprocessor.

Downstream from the shut off valve 26 is a flow control system thatcontrols the flow of the pharmaceutical gas to the patient through thepatient device 18. In the embodiment shown, the flow control systemcomprises a high flow control valve 28 and a low control valve 30 andjust downstream from the high and low flow control valves 28, 30,respectively, are a high flow orifice 32 and a low flow orifice 34 andthe purpose and use of the high and low flow valves 28, 30 and the highand low flow orifices 32, 34 will be later explained. A gas flow sensor36 is also located in the flow of pharmaceutical gas to the patientdevice 18 and, as shown, is downstream from the flow control system,however, the gas flow sensor 36 may alternatively be located upstream ofthe flow control system.

Next, there is a patient trigger sensor 38. When the patient breathes induring inspiration it creates a small sub atmospheric pressure in thenose or other area where the patient device 18 is located, and hence inthe patient device 18 itself. The patient trigger sensor 38 detects thispressure drop and provides a signal indicative of the start ofinspiration of the patient. Similarly, when the patient breathes outthere is a positive pressure in the patient device 18 and the patienttrigger sensor 38 detects that positive pressure and provides a signalindicative of the beginning of expiration. This allows the patienttrigger sensor 38 to determine not only the respiratory rate of thepatient but also the inspiratory and expiratory times.

Finally there is a CPU 40 that communicates with the patient triggersensor 38, the high and low flow valves 28, 30, the gas shut off valve26 and other components in order to carry out the purpose and intent ofthe present invention. The CPU 40 may include a processing componentsuch as a microprocessor to carry out all of the solutions to theequations that are used by the gas delivery system 22 to deliver thepredetermined quantity of the pharmaceutical gas to a patient. The CPU40 is connected to the front panel 10 where the user can enter settingsand monitor therapy.

The use of the delivery system 22 of the present invention forspontaneous breathing can now be explained. When the delivery system 22detects by means of the patient trigger sensor 38 that inspiration hasstarted, there is a signal that is provided to the CPU 40 to deliver adose of a pharmaceutical gas (M_(CO) breath) into the patient'sinspiratory gas flow, preferably during the first ½ of the inspiratorycycle. This amount per breath has been determined based on the desiredquantity of pharmaceutical gas that has been set on the system and thecalculations made in a) to g) described earlier.

The actual volume of gas delivered during the breath depends on theconcentration of the pharmaceutical gas in the carrier gas that issupplied by the supply tank 20. A typical source concentration (C_(CO))for CO would be 3000 ppm (range 500 to 5000). The volume of source gas(V_(d)) per breath to provide a dose per breath (M_(CO) breath) when thesource of CO is 3000 ppm is given by the following equation, combiningequations 2, 3, 4 and 6;

V _(d) =M _(CO breath)/(28·C _(CO)·4.16·10⁻¹¹)   (8)

Given that M_(CO)=60×10⁻³ (g), C_(CO)=3000 (ppm), n_(breaths)=600, thenV_(d)=28.6 (mL).

To deliver the volume of source gas per breath (V_(d)), that is, thepharmaceutical gas and the carrier gas, the delivery system 22 opens aflow control valve, such as high flow valve 28 or low flow valve 30 toallow the gas to flow to the patient until the volume per breath (V_(d))has been delivered. The presence of the high flow orifice 32 and the lowflow orifice 36 limits the flow of gas to a fixed set level during theperiod that the high or low flow valves 28, 30 are open so the deliverysystem 22 can determine the period of time the high or low flow valves28, 30 should be open to deliver the volume per breath (V_(d)) required.Also, as another option, the flow can be determined by the gas flowsensor 36 to monitor the gas flow to the patient device 18 and thus tothe patient and can shut off the appropriate high or low flow controlvalve 28, 30 when the desired predetermined quantity of pharmaceuticalgas dose has been delivered to the patient.

As can be seen, to provide enough range to cover all the possible doses,the use of multiple flow valves, that is, the high flow valve 28 and thelow flow valve 30 along with corresponding multiple orifices, high floworifice 32 and low flow orifice 34, can be used in parallel so as toprovide high and low ranges of gas flow. For instance, the low flow gasflow through the low flow valve 30 could be set to 1 L/min and the highflow gas flow through the high flow control valve 28 could be set to 6L/min. The flow range of the particular gas flow valve is selected toensure that the volume of gas per breath (V_(d)) can be delivered to thepatient in at least ½ the inspiratory time.

As an example, if the patient was breathing at 12 breaths per minute andhad an I:E ratio of 1:2 then the inspiratory time would be 1.66 secondsand half that would be 0.83 seconds.

The time (t) taken to deliver a V_(d) of 28 mL can be calculated asfollows.

t=V _(d)60/(Q·1000) (secs)   (9)

When Q (the flow of gas when the high flow valve 28 is open)=6 L/minst=0.28 (secs).

That time is therefore well within ½ the inspiratory time allowed of0.83 seconds.

The delivery system 22 can also include monitoring and alarm features toalert the user if the delivery system 22 is not working correctly. Thosealarm conditions can be determined by the CPU 40 and the alarm 42activated to alert the user to the particular fault condition. The alarm42 can be audible, visual or both and the alarm conditions can be anyone or all of the following: no breath detected, low source gaspressure, inaccurate delivery of the volume per breath (V_(d)), overdelivery of the volume per breath (V_(d)), under delivery of the volumeper breath (V_(d)) and termination/completion of the delivery program.

Under certain conditions, such as when the delivery system 22 is overdelivering the pharmaceutical gas, the CPU 40 may signal the gas shutoff valve 26 and immediately cease any further delivery of thepharmaceutical gas and the alarm 42 also activated.

The use of the alarm 42 can also be an alternative to actually shuttingoff the supply of the pharmaceutical gas to a patient when thepredetermined desired quantity of pharmaceutical gas has been fullydelivered to the patient. In such case, as an alternative to ceasing thefurther supply of the pharmaceutical gas to the patient, the deliverysystem 22 may, by means of the CPU 40, activate the alarm 42 to alertthe user that the total predetermined desired quantity of thepharmaceutical gas has been delivered. The user can then determinewhether to manually deactivate the delivery system 22 or continue thedelivery of the pharmaceutical gas under more watchful control of thepatient's status.

Turning now to FIG. 4, there is shown a schematic view of a gas deliverysystem 44 used in conjunction with a patient being breathed by aventilator 46. In the FIG. 4 embodiment, again there is a supply tank 20that includes a conventional gas regulator 23 and pressure gauge 21 tosupply the pharmaceutical gas along with the carrier gas to an inlet 24in the gas delivery system 44. Briefly summarizing the components of theFIG. 4 embodiment, since they are basically the same components asdescribed with respect to the FIG. 3 embodiment, there can be a filter25 and a pressure sensor 27 in the gas delivery system 44. Again thereis a shut off valve 26 to control the overall flow of the pharmaceuticalgas through the gas delivery system 44.

The high and low flow control valves 28 and 30 control the flow of thepharmaceutical gas through the gas delivery system 44 and, the high andlow flow valves 28, 30 operate as described with respect to the FIG. 3embodiment with high and low flow orifices 32, 34 located downstream ofthe flow control valves.

Again there is a gas flow sensor 36 and a patient trigger sensor 66,both of which communicate with the CPU 40. With this embodiment,however, the pharmaceutical gas is carried through an outlet conduit 70to a patient device 72 that also receives the breathing gas from theventilator 46. As such, the ventilator 46 delivers a flow of gas throughthe inspiratory limb 74 and gas is returned to the ventilator 46 throughthe expiratory limb 76.

The flow of gas from the ventilator 46 is thus supplemented by the flowof pharmaceutical gas from the gas delivery system 44 where that gas ismixed at or proximate to the patient device 72 for introduction into thepatient 78. Since all of the pharmaceutical gas is still delivered tothe patient over the plurality of breaths, basically the CPU 40 cancarry out the same determination of flows and the like as explained withrespect to the FIG. 3 embodiment. The main difference between this FIG.4 embodiment, and that shown in FIG. 3 is that the patient triggersensor 66 is designed to operate in a way that works with a ventilator46.

For instance, when the ventilator 46 provides gas flow to a patientduring inspiration, it causes a positive pressure in the breathingcircuit. The positive pressure is conducted through the outlet conduit70 and is detected by the patient trigger sensor 66 and is recognized asthe start of inspiration. This is the opposite to the embodiment of FIG.3 where the patient breathes spontaneously and a negative pressure isgenerated during inspiration in the patient device 18; this negativepressure is conducted to the patient trigger sensor 38 of FIG. 3 and isrecognized as the start of inspiration. As can be appreciated, thepatient trigger sensor 38 of FIG. 3 and the patient trigger sensor ofFIG. 4 could be the same pressure sensor and the gas delivery system 44can be set for work with a ventilator or a spontaneously breathingpatient.

One or more embodiments of the invention are directed to methods ofadministering a therapy gas to a patient. A desired total quantity oftherapy gas to be administered to the patient over a period of time overa plurality of breaths is determined. The desired total quantity oftherapy gas can be measured in any suitable units including, but notlimited to, mass of therapy gas, mass of the therapy gas activeingredient and moles of the therapy gas active ingredient. The desiredtotal quantity of therapy gas to be administered to the patient can beentered directly into the device or can be calculated by the device. Forexample, one or more of the following parameters may be input to thedevice: (a) the desired total quantity of therapy gas; (b) the period oftime for delivery of the therapy gas; (c) the total number of breathsover which the delivery gas is delivered; and (d) the frequency ofadministration, i.e. choose the value of n such that the therapy gas isdelivered every n^(th) breath, wherein n is 1 or greater. Treatment maybe repeated as necessary. It will be understood by those skilled in theart that other parameters may be entered.

The quantity of the therapy gas is delivered to the patient duringinspiration. In one or more embodiments, the therapy gas is delivered tothe patient's alveoli. In specific embodiments, substantially all of thetherapy gas is delivered to the patient's alveoli. As used in thisspecification and the appended claims, the term “substantially all”means that at least about 80%, 85%, 90% or 95% of the therapy gas isdelivered to the alveoli. In some embodiments, “substantially all” meansthat a sufficient percentage of therapy gas is delivered to the alveoliso that there is little or no irritation of the respiratory track.

Delivery of the therapy gas to the patient happens every n^(th) breathduring the plurality of breaths. In detailed embodiments, n is 1 orgreater. When n is 1, the therapy gas is delivered to the patient oneach breath. Where n is 2, the therapy gas is delivered to the patienton every other breath. In various embodiments, n is 1, 2, 3, 4, 5, 6, 7,8, 9 or 10. Thus, when n is 2 or greater, conditions of skippedbreathing are achieved, meaning therapy gas is skipped on certainbreaths while administered on certain other breaths. Additionally, theinterval between delivery breaths can vary throughout the delivery ofthe total quantity depending on a number of conditions. For example,therapy gas may be delivered on breaths 1, 3, 5, 8, 10, 12, etc. Indetailed embodiments, the administration of the therapy gas is repeatedfor each n^(th) breath. In various embodiments, the therapy gas isdelivered for 2 out of every 3 breaths, or for 3 out of every 5 breaths,or for 4 out of every 7 breaths, or for 2 out of every 5 breaths, or for2 out of every 7 breaths, etc.

Furthermore, certain embodiments provide that the delivery every n^(th)breath does not need to follow a specific pattern. For example, asdiscussed in more detail below, certain breaths may be skipped for avariety of reasons, such as an amount to be delivered in a particularbreath being less than a minimum delivery quantity. Breaths may also beskipped such that the gas is not delivered on literally every n^(th)breath, but the therapy gas is delivered on average every n^(th) breath.Also, the value of n may change during administration such that thetherapy gas is delivered is every n₁ ^(th) breath for part of theadministration, the therapy gas is delivered is every n₂ ^(th) breathfor another part of the administration, the therapy gas is deliveredevery n₃ ^(th) breath for a third part of the administration, etc.

In some embodiments, the quantity of therapy gas provided at the n^(th)breath is a function of one or more of a first respiratory rate, a firsttidal volume of the patient and the patient's ideal body weight. Thefirst respiratory rate and tidal volume can be measured prior to, at thebeginning of, or during the treatment. One or more of the firstrespiratory rate and tidal volume can be used to calculate an initialamount of therapy gas to be delivered on each n^(th) breath for a periodof time to deliver the desired total quantity of therapy gas. After thisinitial respiratory rate is measured and the initial amount to bedelivered per n^(th) breath is calculated or determined, changes in therespiratory rate may occur and the calculated amount may need to beadjusted. Thus, a subsequent calculation of the amount of therapy gas tobe delivered can be performed. The subsequent calculation can be doneafter any or all individual administration of therapy gas. In oneembodiment, the amount of therapy gas to be delivered during the n^(th)breath can be recalculated after each individual delivery. As a resultof the recalculations, the total quantity of therapy gas delivered isindependent of the patient's respiratory rate, and the total quantity oftherapy gas can be controlled to be the desired amount.

As an example, should the initial amount of therapy gas to be deliveredduring the n^(th) breath be calculated to amount to 100 μL, and afterthe first breath, the patients respiratory rate doubles, the subsequentcalculated rate would be about 50 μL per n^(th) breath. In the priorart, which does not recalculate the amount of therapy gas to bedelivered, this scenario would result in the patient having receivedabout twice the amount of therapy gas as was originally intended by theend of the period of time for delivery of the gas. Thus, recalculatingthe amount of gas to be delivered throughout the delivery period mayresult in a more accurate amount of therapy gas provided to the patientand can help mitigate potential side effects of too much of the therapygas. Accordingly, varying the amount per n^(th) breath ensures that thedesired total amount of therapy gas is delivered to the patient over theplurality of breaths.

The quantity of the therapy gas per n^(th) breath can be varied toensure that the desired total quantity over the period of time isadministered, independent of the respiratory pattern of the patient. Thequantity of therapy gas delivered may be in the range of a minimumquantity and a maximum quantity. In detailed embodiments, the minimumquantity and maximum quantity are functions of the device delivering thetherapy gas. The minimum quantity may be the smallest amount that thedevice is capable of providing and the maximum quantity may be themaximum amount that the device is capable of providing. For example, ifthe smallest volume of therapy gas that the device is capable ofreleasing is 10 μL, then the concentration of the therapy gas multipliedby the smallest deliverable volume will give the smallest amount oftherapy gas active that can be delivered.

In some embodiments, when the quantity of therapy gas to be deliveredper n^(th) breath is greater than the minimum quantity and less than themaximum quantity, the quantity of therapy gas per breath is administeredon the n^(th) breath. When the quantity of therapy gas per n^(th) breathis less than the minimum, the therapy gas can be administered in manyways. For example, if the device is only capable of delivering a minimumof 10 μL, but the quantity to be delivered is 8 μL, the device can skipthe amount to be delivered during this breath and add the amount (8 μL)to any of the subsequent breaths, or can divide the amount among two ormore subsequent breaths. Alternatively, the device can deliver theminimum amount to be delivered (10 μL) and subtract the difference (2μL) from a subsequent breath or divided the amount to be subtracted overtwo or more subsequent breaths. In detailed embodiments, the quantity oftherapy gas per breath is skipped and a new quantity of therapy gas perbreath is calculated for subsequent doses. The new quantity can includethe skipped amount in a single breath, or the new quantity can spreadthe skipped amount over multiple breaths.

When the quantity of therapy gas to be delivered for the n^(th) breathis greater than the maximum quantity, several potential courses ofaction can be taken, including triggering an alarm. In detailedembodiments, the maximum quantity of therapy gas per breath isadministered and the difference between the calculated quantity oftherapy gas for the n^(th) breath and the maximum quantity of therapygas is carried forward for later delivery on one or more subsequentbreaths. However, where later delivery is not possible, the system maytrigger one of many alarm conditions or can be set to automaticallyextend the period of time for delivery to ensure that the desired totalamount of therapy gas is delivered.

In some embodiments, n is 1 such that the therapy gas is administeredevery breath. However, even if the therapy gas is set to be administeredevery breath, some breaths may be skipped if the amount to be deliveredin a given breath is less than the minimum quantity. As noted above, thequantity that would have been delivered during this skipped breath maybe added to any of the subsequent breaths or may be divided among two ormore subsequent breaths.

In some embodiments, the therapy gas is administered every n^(th) breathwhere n is 2 or greater. This means that the therapy gas is provided ina “skip breathing” regimen. Skip breathing may be desired as there canbe an overall decrease in the amount and severity of adverse reactionsincluding irritation due to the therapy gas. In some embodiments, wheren is 2 or greater, the therapy gas is delivered during every other (forn=2) breath, or greater, and no therapy gas is administered during theother breaths. During the alternate breaths (i.e., where no therapy gasis provided) the patient can breathe ambient air, oxygenated air, pureoxygen, or a different therapy gas, depending on the desired treatment.In detailed embodiments, the patient breathes ambient air on inhalationsnot accompanied by therapy gas.

In some embodiments, where n is 2 or greater, the administration ofquantities greater than the maximum amount can be handled differentlythan when therapy gas is delivered on every breath. If the amount to bedelivered is greater than the maximum, the device may proceed in one ormore of the following manners: (a) an alarm can be activated; (b) themaximum amount of therapy gas that can be delivered is delivered to thepatient on the n^(th) breath; and (c) the difference between the maximumamount and the quantity to be delivered is carried over to subsequentbreaths or administrations. If the following breath is skipped as partof a skip breathing protocol, i.e. is not an n^(th) breath, thecarryover dose could be provided during the skipped breath or maintaineduntil the next breath scheduled for dosing.

The amount of therapy gas to be delivered can be calculated multipletimes during the total administration time. The amount can berecalculated based on the number of breaths, the amount of time betweenmeasurements and after every breath, as desired by the administrationprotocol. When the quantity of the therapy gas to be delivered isskipped, for any reason, a new quantity of therapy gas per breath iscalculated.

Upon completion of the administration program, one or more of severalactions can be taken by the device. The device can trigger an alarm, asdescribed earlier. The administration can continue until manually orprogrammatically stopped. The delivery program (i.e., the amount oftherapy gas per period of time) can be repeated for any number ofrepetitions, or indefinitely. The administration of the therapy gas canbe stopped until manually or programmatically restarted (i.e., aprogrammed pause between executions of the administration protocol). Forexample, if the program calls for delivery over a one hour period, thedevice can be programmed to wait for a specified period (e.g., 2 hours)after completion before restarting the administration program.

Additional embodiments of the invention are directed to methods oftreating pulmonary arterial hypertension (PAH), including thosesuffering from chronic obstructive pulmonary disease (COPD), idiopathicpulmonary fibrosis (IPF), etc. A desired total quantity of therapy gasto be delivered to a COPD patient over a period of time over a pluralityof breaths is determined. The quantity is administered to the patientduring inspiration every n^(th) breath of the plurality of breaths,where n is 2 or greater. The quantity of therapy gas is varied perbreath to ensure that the desired total quantity delivered over theperiod of time is maintained independent of the respiratory pattern ofthe patient. In detailed embodiments, varying the quantity of thetherapy gas per breath comprises determining the quantity of therapy gasto be delivered during the breath based on the respiratory rate of thepatient and the amount of therapy gas already given to the patient. Inother words, the desired total amount of therapy gas to be delivered tothe patient over the plurality of breaths is ensured by varying theamount delivered per breath, as required by changes in the breathingpattern of the patient.

FIG. 5 shows a flowchart for a detailed method 100 in accordance withone or more embodiments of the invention. It will be understood by thoseskilled in the art that the method outlined in FIG. 5 is merely apossible methodology and should not be taken as limiting the scope ofthe invention. The methods described provide for ability to manage thetotal quantity of therapy gas given over a period of time. Pertinentinformation related to the administration of the therapy gas and theprogram conditions 102 are entered into a device capable of deliveringthe therapy gas. The program conditions can explicitly state thenecessary information for delivery, or can provide variables which thedevice can use to calculate the necessary information.

The device determines if the approaching breath is an n^(th) breath 104,meaning that the device will administer the therapy gas on that breath.On a first pass through the process flow, the answer will likely be yes,leading the device to determine one or more physiological parameters 106of the patient (e.g., respiratory rate and tidal volume). Thephysiological parameters can be measured by the device or transferredfrom another measuring device or can be manually entered into thedevice.

Based on the measurements of the physiological parameters, the devicecan calculate the amount of therapy gas to be delivered to the patient108. This can be an initial calculation or a subsequent calculation. Thecalculated amount of therapy gas per breath may be compared 110 to aminimum quantity and a maximum quantity of deliverable gas. The minimumand maximum quantities, as described previously, can be functions of thedevice, functions of the concentration of the therapy gas source, afunction of the physiological parameters of the patient and combinationsthereof. If the amount of therapy gas to be delivered is between theminimum and maximum quantities, the dose of therapy gas is delivered 112to the patient on the next breath.

If the comparison in 110 indicated that the amount of therapy gas to bedelivered is less than the minimum deliverable amount, the device canproceed with any or all of several below minimum amount options 114. Thedevice can withhold administration 116 of the therapy gas for thatbreath. The device can carryover 118 the amount not administered to oneor more subsequent breaths. The minimum amount can be administered 120resulting in an over-administration for that breath. The amountover-administered can then be reduced from one or more subsequentbreaths. An alarm condition 122 (e.g., audible, visual, or electronic),as described earlier, can be activated.

If the comparison in 110 indicates that the amount of therapy gas to bedelivered is greater than the maximum deliverable amount, the device canproceed with any or all of several above maximum amount options 124. Thedevice can trigger an alarm condition 122 as described above. The devicecan administer the maximum amount 126 and either discard the differenceor carryover 118 the difference to subsequent breaths. However,depending on the reason for the quantity to be delivered to be over themaximum and the administration protocol, carrying over the difference tosubsequent breaths can result in the amount for each n^(th) breath to beover the maximum. To avoid this, the device can be programmed tocarryover the amount if, for example, the calculated amount to bedelivered is an outlier or if subsequent breaths are skipped.

After the amount of therapy gas is delivered (if applicable), the devicedetermines if it has reached the end conditions 128 of the program(e.g., time, amount delivered, number of breaths). If the end conditionhas not been reached, the device can then check to see if the nextbreath is scheduled to receive a dose of therapy gas 104. If yes, themethod proceeds through one or more of the steps as previouslydescribed. If the following breath is not supposed to receive therapygas, the device can determine if there is carryover from a previousbreath 130. If there is carryover and it is the delivery of therapy gasis allowed on the alternate breaths, the device can determine the amountof therapy gas per breath to deliver 108. This can be as simple asdelivering the carried over amount, or holding the amount for furthersubsequent breaths. If there are no carry over breaths 130, the devicecan do nothing for the breath and restart the method at evaluating ifthe next breath is an n^(th) breath 104.

When the end conditions 128 have been met, the method and device canproceed through one or more of various end condition actions 132. Thedelivery of the therapy gas can be discontinued until manually orprogrammatically restarted 134. An alarm can be triggered.Administration of the therapy gas can continue 136 under the sameconditions (e.g., restarting the program 138) or with differentconditions.

Those skilled in the art will readily recognize numerous adaptations andmodifications which can be made to the pharmaceutical gas deliverysystem and method of delivering a pharmaceutical gas of the presentinvention which will result in an improved method and system forintroducing a known desired quantity of a pharmaceutical gas into apatient, yet all of which will fall within the scope and spirit of thepresent invention as defined in the following claims. Accordingly, theinvention is to be limited only by the following claims and theirequivalents.

What is claimed is:
 1. A method of administering a pharmaceutical gas toa patient, wherein the pharmaceutical gas comprises at least one ofnitric oxide or carbon monoxide, the method comprising: delivering afirst quantity of the pharmaceutical gas to the patient in a firstbreath; monitoring the patient's respiratory rate or changes in thepatient's respiratory rate; varying the quantity of pharmaceutical gasdelivered to the patient in one or more subsequent breaths based on themonitored respiratory rate or changes in the patient's respiratory rate.2. The method of claim 1, wherein the quantity delivered in thesubsequent breath is greater than the first quantity in response to adecrease in the patient's respiratory rate.
 3. The method of claim 1,wherein the quantity delivered in the subsequent breath is less than thefirst quantity in response to an increase in the patient's respiratoryrate.
 4. The method of claim 1, wherein varying the quantity ofpharmaceutical gas delivered to the patient avoids high unsafe doses ordoses too low to be effective.
 5. The method of claim 1, wherein thepharmaceutical gas is delivered to the patient every breath.
 6. Themethod of claim 1, wherein the pharmaceutical gas is delivered to thepatient every nth breath, wherein n is 1 or greater.
 7. The method ofclaim 1, wherein at least one breath is skipped such that pharmaceuticalgas is not administered during the breath.
 8. The method of claim 7,wherein when the breath is skipped, a new quantity of pharmaceutical gasper nth breath is calculated.
 9. The method of claim 1, wherein when thequantity of pharmaceutical gas to be delivered in a breath is greaterthan a maximum quantity of pharmaceutical gas per breath, the maximumquantity of pharmaceutical gas per breath is administered and thedifference between the quantity of pharmaceutical gas to be delivered inthe breath and the maximum quantity of pharmaceutical gas per breath isadded to one or more subsequent breaths.
 10. The method of claim 1,wherein one or more of the first quantity and the quantity delivered inthe subsequent breath is delivered during the first half of inspiration.11. A gas delivery system comprising: an inlet to connect to a source ofpharmaceutical gas comprising at least one of nitric oxide or carbonmonoxide; an outlet to connect to a device that introduces thepharmaceutical gas to a patient; a breath trigger sensor to measure apatient's respiratory rate; and a gas control system in communicationwith the breath trigger sensor that delivers a varying quantity ofpharmaceutical gas to the patient based on changes in the patient'srespiratory rate.
 12. The system of claim 11, wherein a quantitydelivered in a subsequent breath is greater than a quantity delivered ina previous breath in response to a decrease in the patient's respiratoryrate.
 13. The system of claim 11, wherein a quantity delivered in asubsequent breath is less than a quantity delivered in a previous breathin response to an increase in the patient's respiratory rate.
 14. Thesystem of claim 11, wherein the gas control system delivers the quantityof pharmaceutical gas during the first half of the patient's inspiratorycycle.
 15. The system of claim 11, wherein the gas control systemdelivers the pharmaceutical gas to the patient every breath.
 16. Thesystem of claim 11, wherein delivering a varying quantity ofpharmaceutical gas to the patient avoids high unsafe doses or doses toolow to be effective.
 17. The system of claim 11, wherein thepharmaceutical gas is delivered to the patient every nth breath, whereinn is 1 or greater.
 18. The system of claim 11, wherein at least onebreath is skipped such that pharmaceutical gas is not administeredduring the breath.
 19. The system of claim 18, wherein when the breathis skipped, a new quantity of pharmaceutical gas per nth breath iscalculated.
 20. The system of claim 11, wherein when a quantity ofpharmaceutical gas to be delivered in a breath is greater than a maximumquantity of pharmaceutical gas per breath, the maximum quantity ofpharmaceutical gas per breath is administered and the difference betweenthe quantity of pharmaceutical gas to be delivered in the breath and themaximum quantity of pharmaceutical gas per breath is added to one ormore subsequent breaths.